Browsing by Author "Chen, Qiang"

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Open Access
Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response.
(Molecular and cellular biology, 2016-07) Reid, David W; Tay, Angeline SL; Sundaram, Jeyapriya R; Lee, Irene CJ; Chen, Qiang; George, Simi E; Nicchitta, Christopher V; Shenolikar, Shirish
Phosphorylation of eukaryotic initiation factor 2α (eIF2α) controls transcriptome-wide changes in mRNA translation in stressed cells. While phosphorylated eIF2α (P-eIF2α) attenuates global protein synthesis, mRNAs encoding stress proteins are more efficiently translated. Two eIF2α phosphatases, containing GADD34 and CReP, catalyze P-eIF2α dephosphorylation. The current view of GADD34, whose transcription is stress induced, is that it functions in a feedback loop to resolve cell stress. In contrast, CReP, which is constitutively expressed, controls basal P-eIF2α levels in unstressed cells. Our studies show that GADD34 drives substantial changes in mRNA translation in unstressed cells, particularly targeting the secretome. Following activation of the unfolded protein response (UPR), rapid translation of GADD34 mRNA occurs and GADD34 is essential for UPR progression. In the absence of GADD34, eIF2α phosphorylation is persistently enhanced and the UPR translational program is significantly attenuated. This "stalled" UPR is relieved by the subsequent activation of compensatory mechanisms that include AKT-mediated suppression of PKR-like kinase (PERK) and increased expression of CReP mRNA, partially restoring protein synthesis. Our studies highlight the coordinate regulation of UPR by the GADD34- and CReP-containing eIF2α phosphatases to control cell viability.
Open Access
Study in vitro and in vivo of nociceptin/orphanin FQ(1-13)NH2 analogues substituting N-Me-Gly for Gly2 or Gly3.
(Peptides, 2004-08) Chen, Li-xiang; Fang, Quan; Chen, Qiang; Guo, Jia; Wang, Zhuan-zi; Chen, Yong; Wang, Rui
In the present study, two analogues containing N-Me-Gly (Sarcosine, Sar) were synthesized to further investigate the structural-activity relationships of orphanin FQ/nociceptin (OFQ/NC, NC). The replacement of Gly(2) or Gly(3) with Sar increased the flexibility and decreased the hydrophobicity of the N-terminal tetrapeptide. The activity of the analogues was investigated in a series of assays in vivo and in vitro. [Sar(2)]NC(1-13)NH(2) was found to (1) produce dose-dependent inhibition of the electrically induced contraction in MVD assay (pEC(50) = 6.14); (2) produce significant hyperalgesia effects in a dose-dependent manner when intracerebroventricularly (i.c.v.) injected in mice. The inhibitive effects of [Sar(2)]NC(1-13)NH(2) in MVD assay could be significantly antagonized by [Nphe(1)]NC(1-13)NH(2), and partially antagonized by naloxone; the hyperalgesic effect of [Sar(2)]NC(1-13)NH(2) could be significantly antagonized by naloxone, and partially antagonized by [Nphe(1)]NC(1-13)NH(2). On the contrary, [Sar(3)]NC(1-13)NH(2) showed no effects in these assays. All the findings suggest that the flexibility of the peptide bond between Phe(1) and Gly(2) and between Gly(2) and Gly(3) play an important role in NC-OP(4) receptor interaction, and the hydrophobicity of the N-terminal tetrapeptide showed no significant effect on this interaction. The present work also helps to provide a novel method to elucidate structural and conformational requirements of the opioid peptide-receptor interaction.
Open Access
The genetic architecture of the human cerebral cortex.
(Science (New York, N.Y.), 2020-03) Grasby, Katrina L; Jahanshad, Neda; Painter, Jodie N; Colodro-Conde, Lucía; Bralten, Janita; Hibar, Derrek P; Lind, Penelope A; Pizzagalli, Fabrizio; Ching, Christopher RK; McMahon, Mary Agnes B; Shatokhina, Natalia; Zsembik, Leo CP; Thomopoulos, Sophia I; Zhu, Alyssa H; Strike, Lachlan T; Agartz, Ingrid; Alhusaini, Saud; Almeida, Marcio AA; Alnæs, Dag; Amlien, Inge K; Andersson, Micael; Ard, Tyler; Armstrong, Nicola J; Ashley-Koch, Allison; Atkins, Joshua R; Bernard, Manon; Brouwer, Rachel M; Buimer, Elizabeth EL; Bülow, Robin; Bürger, Christian; Cannon, Dara M; Chakravarty, Mallar; Chen, Qiang; Cheung, Joshua W; Couvy-Duchesne, Baptiste; Dale, Anders M; Dalvie, Shareefa; de Araujo, Tânia K; de Zubicaray, Greig I; de Zwarte, Sonja MC; den Braber, Anouk; Doan, Nhat Trung; Dohm, Katharina; Ehrlich, Stefan; Engelbrecht, Hannah-Ruth; Erk, Susanne; Fan, Chun Chieh; Fedko, Iryna O; Foley, Sonya F; Ford, Judith M; Fukunaga, Masaki; Garrett, Melanie E; Ge, Tian; Giddaluru, Sudheer; Goldman, Aaron L; Green, Melissa J; Groenewold, Nynke A; Grotegerd, Dominik; Gurholt, Tiril P; Gutman, Boris A; Hansell, Narelle K; Harris, Mathew A; Harrison, Marc B; Haswell, Courtney C; Hauser, Michael; Herms, Stefan; Heslenfeld, Dirk J; Ho, New Fei; Hoehn, David; Hoffmann, Per; Holleran, Laurena; Hoogman, Martine; Hottenga, Jouke-Jan; Ikeda, Masashi; Janowitz, Deborah; Jansen, Iris E; Jia, Tianye; Jockwitz, Christiane; Kanai, Ryota; Karama, Sherif; Kasperaviciute, Dalia; Kaufmann, Tobias; Kelly, Sinead; Kikuchi, Masataka; Klein, Marieke; Knapp, Michael; Knodt, Annchen R; Krämer, Bernd; Lam, Max; Lancaster, Thomas M; Lee, Phil H; Lett, Tristram A; Lewis, Lindsay B; Lopes-Cendes, Iscia; Luciano, Michelle; Macciardi, Fabio; Marquand, Andre F; Mathias, Samuel R; Melzer, Tracy R; Milaneschi, Yuri; Mirza-Schreiber, Nazanin; Moreira, Jose CV; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Najt, Pablo; Nakahara, Soichiro; Nho, Kwangsik; Olde Loohuis, Loes M; Orfanos, Dimitri Papadopoulos; Pearson, John F; Pitcher, Toni L; Pütz, Benno; Quidé, Yann; Ragothaman, Anjanibhargavi; Rashid, Faisal M; Reay, William R; Redlich, Ronny; Reinbold, Céline S; Repple, Jonathan; Richard, Geneviève; Riedel, Brandalyn C; Risacher, Shannon L; Rocha, Cristiane S; Mota, Nina Roth; Salminen, Lauren; Saremi, Arvin; Saykin, Andrew J; Schlag, Fenja; Schmaal, Lianne; Schofield, Peter R; Secolin, Rodrigo; Shapland, Chin Yang; Shen, Li; Shin, Jean; Shumskaya, Elena; Sønderby, Ida E; Sprooten, Emma; Tansey, Katherine E; Teumer, Alexander; Thalamuthu, Anbupalam; Tordesillas-Gutiérrez, Diana; Turner, Jessica A; Uhlmann, Anne; Vallerga, Costanza Ludovica; van der Meer, Dennis; van Donkelaar, Marjolein MJ; van Eijk, Liza; van Erp, Theo GM; van Haren, Neeltje EM; van Rooij, Daan; van Tol, Marie-José; Veldink, Jan H; Verhoef, Ellen; Walton, Esther; Wang, Mingyuan; Wang, Yunpeng; Wardlaw, Joanna M; Wen, Wei; Westlye, Lars T; Whelan, Christopher D; Witt, Stephanie H; Wittfeld, Katharina; Wolf, Christiane; Wolfers, Thomas; Wu, Jing Qin; Yasuda, Clarissa L; Zaremba, Dario; Zhang, Zuo; Zwiers, Marcel P; Artiges, Eric; Assareh, Amelia A; Ayesa-Arriola, Rosa; Belger, Aysenil; Brandt, Christine L; Brown, Gregory G; Cichon, Sven; Curran, Joanne E; Davies, Gareth E; Degenhardt, Franziska; Dennis, Michelle F; Dietsche, Bruno; Djurovic, Srdjan; Doherty, Colin P; Espiritu, Ryan; Garijo, Daniel; Gil, Yolanda; Gowland, Penny A; Green, Robert C; Häusler, Alexander N; Heindel, Walter; Ho, Beng-Choon; Hoffmann, Wolfgang U; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Jack, Clifford R; Jang, MiHyun; Jansen, Andreas; Kimbrel, Nathan A; Kolskår, Knut; Koops, Sanne; Krug, Axel; Lim, Kelvin O; Luykx, Jurjen J; Mathalon, Daniel H; Mather, Karen A; Mattay, Venkata S; Matthews, Sarah; Mayoral Van Son, Jaqueline; McEwen, Sarah C; Melle, Ingrid; Morris, Derek W; Mueller, Bryon A; Nauck, Matthias; Nordvik, Jan E; Nöthen, Markus M; O'Leary, Daniel S; Opel, Nils; Martinot, Marie-Laure Paillère; Pike, G Bruce; Preda, Adrian; Quinlan, Erin B; Rasser, Paul E; Ratnakar, Varun; Reppermund, Simone; Steen, Vidar M; Tooney, Paul A; Torres, Fábio R; Veltman, Dick J; Voyvodic, James T; Whelan, Robert; White, Tonya; Yamamori, Hidenaga; Adams, Hieab HH; Bis, Joshua C; Debette, Stephanie; Decarli, Charles; Fornage, Myriam; Gudnason, Vilmundur; Hofer, Edith; Ikram, M Arfan; Launer, Lenore; Longstreth, WT; Lopez, Oscar L; Mazoyer, Bernard; Mosley, Thomas H; Roshchupkin, Gennady V; Satizabal, Claudia L; Schmidt, Reinhold; Seshadri, Sudha; Yang, Qiong; Alzheimer’s Disease Neuroimaging Initiative; CHARGE Consortium; EPIGEN Consortium; IMAGEN Consortium; SYS Consortium; Parkinson’s Progression Markers Initiative; Alvim, Marina KM; Ames, David; Anderson, Tim J; Andreassen, Ole A; Arias-Vasquez, Alejandro; Bastin, Mark E; Baune, Bernhard T; Beckham, Jean C; Blangero, John; Boomsma, Dorret I; Brodaty, Henry; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bustillo, Juan R; Cahn, Wiepke; Cairns, Murray J; Calhoun, Vince; Carr, Vaughan J; Caseras, Xavier; Caspers, Svenja; Cavalleri, Gianpiero L; Cendes, Fernando; Corvin, Aiden; Crespo-Facorro, Benedicto; Dalrymple-Alford, John C; Dannlowski, Udo; de Geus, Eco JC; Deary, Ian J; Delanty, Norman; Depondt, Chantal; Desrivières, Sylvane; Donohoe, Gary; Espeseth, Thomas; Fernández, Guillén; Fisher, Simon E; Flor, Herta; Forstner, Andreas J; Francks, Clyde; Franke, Barbara; Glahn, David C; Gollub, Randy L; Grabe, Hans J; Gruber, Oliver; Håberg, Asta K; Hariri, Ahmad R; Hartman, Catharina A; Hashimoto, Ryota; Heinz, Andreas; Henskens, Frans A; Hillegers, Manon HJ; Hoekstra, Pieter J; Holmes, Avram J; Hong, L Elliot; Hopkins, William D; Hulshoff Pol, Hilleke E; Jernigan, Terry L; Jönsson, Erik G; Kahn, René S; Kennedy, Martin A; Kircher, Tilo TJ; Kochunov, Peter; Kwok, John BJ; Le Hellard, Stephanie; Loughland, Carmel M; Martin, Nicholas G; Martinot, Jean-Luc; McDonald, Colm; McMahon, Katie L; Meyer-Lindenberg, Andreas; Michie, Patricia T; Morey, Rajendra A; Mowry, Bryan; Nyberg, Lars; Oosterlaan, Jaap; Ophoff, Roel A; Pantelis, Christos; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda WJH; Polderman, Tinca JC; Posthuma, Danielle; Rietschel, Marcella; Roffman, Joshua L; Rowland, Laura M; Sachdev, Perminder S; Sämann, Philipp G; Schall, Ulrich; Schumann, Gunter; Scott, Rodney J; Sim, Kang; Sisodiya, Sanjay M; Smoller, Jordan W; Sommer, Iris E; St Pourcain, Beate; Stein, Dan J; Toga, Arthur W; Trollor, Julian N; Van der Wee, Nic JA; van 't Ent, Dennis; Völzke, Henry; Walter, Henrik; Weber, Bernd; Weinberger, Daniel R; Wright, Margaret J; Zhou, Juan; Stein, Jason L; Thompson, Paul M; Medland, Sarah E; Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group
The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
Open Access
The unfolded protein response triggers selective mRNA release from the endoplasmic reticulum.
(Cell, 2014-09) Reid, David W; Chen, Qiang; Tay, Angeline S-L; Shenolikar, Shirish; Nicchitta, Christopher V
The unfolded protein response (UPR) is a stress response program that reprograms cellular translation and gene expression in response to proteotoxic stress in the endoplasmic reticulum (ER). One of the primary means by which the UPR alleviates this stress is by reducing protein flux into the ER via a general suppression of protein synthesis and ER-specific mRNA degradation. We report here an additional UPR-induced mechanism for the reduction of protein flux into the ER, where mRNAs that encode signal sequences are released from the ER to the cytosol. By removing mRNAs from the site of translocation, this mechanism may serve as a potent means to transiently reduce ER protein folding load and restore proteostasis. These findings identify the dynamic subcellular localization of mRNAs and translation as a selective and rapid regulatory feature of the cellular response to protein folding stress.